While the acute effects of cocaine on brain neurochemistry have been well characterized, much less is known about the long-term changes in neurochemistry and brain function associated with chronic drug use. Clearly, a better understanding of the neurobiology underlying the progression to dependence and addiction will help direct appropriate treatment strategies. Preventing relapse is often the most difficult obstacle in treating drug addiction. It is well recognized that exposure to environmental cues associated with drug use can induce relapse in patients who have been abstinence for extended periods. Virtually nothing is known about the neurobiological underpinnings associated with extinction therapy or its enhancement by pharmacological intervention in the treatment of cocaine abuse and addiction. In the prospective studies proposed in nonhuman primates, we will evaluate changes in neurochemistry, and functional brain activity following limited- and extended-access to cocaine self-administration, drug abstinence, and extinction training with and without pharmacological intervention. Cue-induced reinstatement of cocaine self-administration will provide an abuse-related behavioral outcome to correlate with relevant neurobiological measures. We will document the effects of cocaine exposure and extinction training on 1) extracelluar neurotransmitter and metabolite levels using microdialysis, 2) in vivo binding potential of monoamine transporters and receptors using PET imaging, 3) trafficking capacity of monoamine transporters using PET imaging, 4) cocaine- and cue-induced brain activation using fMRl and, 5) resting state functional activity using fMRl. These studies will also utilize a repeated-measures experimental design, strengthening the significance ofthe results. The proposed research is highly innovative in its focus on abstinence and extinction training and the integration of multiple imaging modalities in a paradigm that models the progression of cocaine use to dependence and addiction. The long-term goals of our research are to gain a greater understanding of the mechanisms of psychostimulant addiction and to identify targets for effective treatment medications.